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Cite This: J. Am. Chem. Soc. 2018, 140, 11931−11934
Acceptorless Dehydrogenative Coupling Using Ammonia: Direct
Synthesis of N‑Heteroaromatics from Diols Catalyzed by Ruthenium
Prosenjit Daw, Yehoshoa Ben-David, and David Milstein*
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
*
S Supporting Information
ABSTRACT: The synthesis of N-heteroaromatic com-
pounds via an acceptorless dehydrogenative coupling
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process involving direct use of ammonia as the nitrogen
source was explored. We report the synthesis of pyrazine
derivatives from 1,2-diols and the synthesis of N-
substituted pyrroles by a multicomponent dehydrogen-
ative coupling of 1,4-diols and primary alcohols with
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ammonia. The acridine-based Ru-pincer complex 1 is an
effective catalyst for these transformations, in which the
acridine backbone is converted to an anionic dearomat-
ized PNP-pincer ligand framework.
A mmonia is the simplest, useful molecule employed as a
nitrogen source in synthesis, with generally high atom
economy.1 It is used for the synthesis of a wide range of
commercially useful products, including amines, amides, ureas,
carbamates, isocyanates, amino acids, N-heteroaromatic, and
heterocyclic compounds.2 Of particular interest and in the
context of sustainable chemistry, environmentally benign
routes to the catalytic synthesis of amines from readily
available alcohols using ammonia and generating no hazardous
waste is of much current attraction. In 2008, we reported the
direct homogeneous catalytic selective amination of primary
alcohols to primary amines using ammonia, catalyzed by an
acridine-based Ru pincer complex (eq 1).3 In 2014, Hofmann
et al. reported a similar acridine-based pincer ruthenium
complex as an effective catalyst for the amination of primary
alcohols using ammonia and also proposed a probable
mechanism based on experimental and density functional
theory (DFT) studies.4 Other research groups also explored
the amination of alcohols using ammonia.5 Multialkylation of
ammonia to form secondary or tertiary amines was developed
using iridium catalysts.6 Our group also developed the
Ru(BpyPNN) pincer catalyst for the synthesis of secondary
amines from the primary alcohols and ammonia.7
Diverse bioactive natural products and pharmaceutically
important, aromatic N-heterocyclic molecules are classically
synthesized by the coupling of ammonia with various carbonyl
derivatives.8 Although extensively used, most of these
protocols suffer from various shortcomings, such as availability
of starting materials, multistep synthetic operations, and
copious waste generation. Thus, alternative strategies involving
© 2018 American Chemical Society
Communication
pubs.acs.org/JACS
sustainable, one-step, atom-economical methodologies for the
preparation of valuable N-heteroaromatic molecules are
needed. In this regard, our group has demonstrated several
environmentally benign reactions involving dehydrogenative
coupling of alcohols and amines, with H2 and water as the sole
byproducts, catalyzed by ruthenium pincer complexes based on
pyridine and acridine backbones.9 Notable progress has been
made in recent years in the sustainable synthesis of N-
heteroaromatic compounds using alcohols and amines based
on acceptorless dehydrogenative coupling pathways.10
The direct use of ammonia in acceptorless dehydrogenative
coupling reactions for the synthesis of N-heteroaromatic
compounds is challenging. Noteworthy, the “glucose-ammonia
model” was established for the synthesis of various pyrazine
derivatives from biomass by using ammonia in the presence of
a metal salt under aerobic conditions. 11 Acceptorless
dehydrogenative coupling reactions are often driven by the
efficient removal of the generated H2 in an open system, which
poses an obvious problem when ammonia gas is used under
pressure in a closed system.
Herein, we present such reactions, including (a) formation
of pyrazine derivatives from 1,2-diols and ammonia and (b)
three-component synthesis of N-substituted pyrroles by the
dehydrogenative coupling of 1,4-diols with primary alcohols
and ammonia (Scheme 1). In both reactions, gaseous ammonia
Scheme 1. Synthesis of Pyrazines and Pyrroles from
Alcohols and Ammonia Catalyzed by a Ruthenium Complex
is the source of nitrogen, and the catalyst is an acridine-based
ruthenium pincer complex, with no additives such as base or
oxidant being required.
The optimized reaction conditions developed by our group
for the amination of alcohols with ammonia3 were explored for
pyrazine formation using 1,2-diols and catalyst 1. Heating a
toluene solution of 1,2-hexanediol (1 mmol) at 150 °C (bath
temperature) with complex 1 (1 mol %) in a Fischer−Porter
Received: August 11, 2018
Published: September 12, 2018
11931 DOI: 10.1021/jacs.8b08385
J. Am. Chem. Soc. 2018, 140, 11931−11934
Journal of the American Chemical Society
tube under 7 bar of ammonia for 36 h resulted in quantitative
consumption of the diol, forming a mixture of 2,6- and 2,5-
dibutylpyrazine (65:35 ratio, respectively), as shown by gas
chromatography−mass spectrometry (GC-MS) and NMR
spectroscopy (Table 1, entry 1). Since pyrazine derivatives
Table 1. Pyrazine Formation by 1,2-Diol and Ammoniaa
a Dehydrogenative Coupling of Alcohols and Ammoniaa
Reaction conditions: Catalyst 1 (0.01 mmol), 1,2-diol (1 mmol),
ammonia (7 bar), 150 °C (bath temp), 36 h, toluene (2 mL).
b
Isolated yield. cGC-MS yield with mesitylene as internal standard.
d
Hydrogenated product.
are of importance as potential bioactive molecules in drug
research12 several vicinal diols were screened. Employing
longer linear alcohols, such as 1,2-decanediol and 1,2-
tetradecanediol, resulted in quantitative conversion to form a
1:1 mixture of both isomers (Table 1, entries 2 and 3). The
reaction with 1-phenyl-1,2-ethanediol afforded quantitative
yields of the corresponding diphenylpyrazine derivatives with
68:32 ratio (Table 1, entry 4). Treatment of 1,2-butanediol
afforded 72% of the diethylpyrazine derivatives, whereas 1,2-
propanediol afforded 42% of the desired product, along with
some unidentified side products in both cases (Table 1, entries
5 and 6). Under the same conditions, ethylene glycol did not
form any pyrazine, although piperazine and its derivatives were
detected as minor products along with some unidentified
polymeric products. 1,2-Disubstituted-1,2-diols are readily
synthesized by direct hydrogenolysis of lignocellulose biomass,
although these sterically hindered diols are challenging
substrates for dehydrogenation. Employing such substrates,
2,3-butanediol afforded 85% of the tetramethylpyrazine as the
major product, whereas reaction of 1,2-cyclohexanediol
resulted in formation of octahydrophenazine in 95% yield
with a minute amount hydrogenated products (entries 7 and
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Communication
8). Formation of octahydrophenazine as a minor product along
with mixture of amines in the amination of 1,2-cyclohexanediol
was reported.5g
Next, we examined the reaction of 1,4-butanediol derivatives
with ammonia, aiming at formation of pyrroles. While reaction
of 1,4-butanediol produced pyrrolidine quantitatively, employ-
ing 2,5-hexanediol resulted in 85% yield of 2,5-dimethyl-1-
pyrroline and 15% yield of the 2,5-dimethylpyrrole under
ammonia pressure using 1 (1 mol %) under the optimized
conditions (see Supporting Information, Figure S1 for details).
Interestingly, when a primary alcohol was added to 2,5-
hexanediol, a multicomponent dehydrogenative coupling
reaction took place, yielding N-substituted pyrroles. Classical
methods for N-substituted pyrrole synthesis involve the Paal−
Knorr reactions.13 Also, the dehydrogenative coupling of 2-
amino alcohol derivatives with secondary alcohols to afford
pyrrole derivatives was reported by Kempe10a and by our
group.10g Recently the dehydrogenative coupling of 1,4-
butanediol derivatives with primary amines was reported.10h,i
To the best of our knowledge, synthesis of N-substituted
pyrroles by dehydrogenative coupling of 1,4-butanediol
derivatives with primary alcohols and ammonia was never
reported. However, we are aware of dehydrogenative coupling
of ketones and primary alcohols to form N-nonsubstituted
pyrrole derivatives using ammonia.10b,c
The optimal reaction conditions were achieved by treatment
of 2,5-hexanediol (1 mmol) and 1-hexanol (2 mmol) using 1
mol % of 1 under 7 bar of ammonia at 150 °C for 24 h in 0.5
mL of toluene, affording 90% of 1-hexyl-2,5-dimethylpyrrole as
the dehydrogenative coupling product (Table 2, entry A; see
the reaction optimization Table S2 in Supporting Informa-
tion). Encouraged by the efficient catalytic three-component
dehydrogenative coupling of alcohols with ammonia to form
Table 2. N-Substituted Pyrrole Formation by
a
Reaction conditions: Catalyst 1 (0.01 mmol), 2,5-hexanediol (1
mmol), primary alcohol (2 mmol), ammonia (7 bar) 150 °C, 24 h,
toluene (0.5 mL), NMR yield with mesitylene as internal standard.
b
Primary alcohol (4 mmol). c1,4-Butanediol (1 mmol). d1-Phenyl-
1,4-pentanediol (1 mmol). e1,4-Diphenyl-1,4-butanediol (1 mmol).
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Journal of the American Chemical Society
pyrroles, various primary alcohols were screened. Under the
optimized reaction conditions 1-octanol, 1-pentanol, and 1-
butanol yielded 83%, 76%, and 77% of the corresponding N-
substituted pyrroles, respectively (Table 2, entries B−D). 3-
(N,N-Dimethyl)amino-1-propanol afforded 74% of the corre-
sponding 1,2,5-substituted pyrrole derivative as the major
product (Table 2, entry E). 2-Phenyl-1-ethanol and 3-phenyl-
1-propanol afforded 76% and 74% of the desired product,
respectively (Table 2, entries F and G). In case of low-boiling
primary alcohols, such as 1-propanol, ethanol, and methanol, 4
equiv of the alcohol with respect to 2,5-hexanediol were used
(see Table 2 footnotes for reaction conditions) and afforded
good-to-moderate yields of the corresponding 1,2,5-substituted
pyrroles (Table 2, entries H−J). Replacement of linear primary
alcohols by benzyl alcohols resulted in lower reactivity under
the same conditions and afforded moderate yield of the 1,2,5-
substituted pyrroles. Reactions of benzyl alcohol and 4-methyl
benzyl alcohol afforded 57% and 48% yields, respectively, of
the corresponding pyrrole derivatives, whereas the bulkier 3,4-
dimethoxybenzyl alcohol afforded only 13% of the product
(Table 2, entries K−M). Under the same reaction conditions,
heteroatom-substituted primary alcohols also showed good
yields. Nicotinyl alcohol and furfuryl alcohol afforded 69% and
84% yields, respectively, of the corresponding 2,5-dimethyl-N-
substituted pyrrole as the major product (Table 2, entries N
and O). The alcohols were fully consumed, and in addition to
the N-substituted 2,5-dimethylpyrrole product, the side
products 2,5-dimethylpyrrole and 2,5-dimethyl-1-pyrroline,
the corresponding primary amine, and a minute amount of
secondary amine of the primary alcohol were also observed in
each case (see Supporting Information, Table S3).
Unlike the other mentioned diols, treatment of 1,4-
butanediol with 2 equiv of 1-hexanol and ammonia formed
N-hexylpyrrolidine as the coupling product (40%) along with
N-hexylpyrrole (10%) and pyrrolidine (Table 2, entry P).
Under the optimized conditions, in the presence of ammonia,
reaction of 1-hexanol with 1-phenyl-1,4-pentanediol afforded
44% of 1-hexyl-2-phenyl-5-methyl pyrrole, whereas 1,4-
diphenyl-1,4-butanediol afforded only 10% yield of the 1-
hexyl-2,5-diphenyl pyrrole with N-nonsubstituted pyrrole and
pyrroline as the major side products (Table 2, entries Q and R;
also, see details in Supporting Information, Figure S2). This is
likely a result of the internal amine attack being preferred in
the case of the more sterically hindered carbonyl moiety as
compared with the external attack, giving a higher yield of the
nonsubstituted pyrrole (see mechanism part).
The mechanism of the direct amination of alcohols by
ammonia to form primary amines (see Supporting Informa-
tion) was well-documented by us3,14 and independently by
Hofmann et al.,4 supported by DFT and experimental
evidence. It was experimentally observed that complex 1 in
the presence of alcohol and ammonia was converted to the
ammonia-coordinated complex 3, containing a dearomatized
acridine backbone ligand (see Supporting Information).
Complex 3 was instantly formed by treatment of complex
214 with ammonia (Scheme 2A; for details, see Supporting
Information). Complex 2 was equally active in the alcohol
amination reaction. Thus, under the optimized conditions, full
conversion of benzyl alcohol yielding 90% of benzylamine and
10% of N-benzylidenebenzylamine took place. However,
treatment of 2,5-hexanediol and 1-hexanol with complex 2
under the optimized condition afforded only 50% of 1-hexyl-
2,5-dimethylpyrrole, whereas enhancement of the yield (68%)
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Communication
Scheme 2. Synthesis of Complex 3 and a Catalytic
Experiment with Catalyst 2
was observed by addition of NH4Cl (2 mol %; Scheme 2B),
which indicates that the eliminated catalytic HCl as NH4Cl
during the alcohol amination using complex 1 (Scheme 2A)
promotes the subsequent reactions leading to pyrazines and
pyrroles.
In the proposed mechanism for pyrazine formation from
vicinal diols and ammonia catalyzed by 1, the primary alcohol
group of the vicinal diol undergoes amination to from a β-
amino secondary alcohol intermediate. Dehydrogenation of the
secondary alcohol group then takes place, followed by self-
coupling to produce 2,5-dihydropyrazine by elimination of two
molecules of water, followed by aromatization by further
dehydrogenation to form the final pyrazine (Scheme 3A).
Scheme 3. Proposed Mechanism
The pyrrole formation reaction involves dehydrogenative
coupling of 2,5-hexanediol and the primary alcohol in the
presence of ammonia and catalyst 1 with H2 and water as the
sole byproducts (Scheme 3B). Analysis of the gas phase by gas
chromatography indicated the formation of H2 (see Figure
S24). Dehydrogenation and amination of the primary alcohol
prevails over that of the secondary alcohol, affording the
corresponding primary amine. Dehydrogenation of the
secondary alcohol group generates a keto intermediate. Two
competitive reactions can take place at this stage. The initially
formed primary amine can attack the keto intermediate,
eliminating two molecules of water to directly form the 1,2,5-
substituted pyrrole as the target product. The second
possibility is the direct ammonia attack on the keto group,
followed by hydrogenation to afford an amine, which attacks
the internal keto group and forms the cyclic 2,5-dimethyl-1-
pyrroline, eliminating water; further dehydrogenation gives the
N−H pyrrole as a side product. Increasing the ratio of primary
alcohol to the 1,4-diol derivative increases the concentration of
the primary amine and favors its attack to form the desired
1,2,5-substituted pyrrole (see reaction optimization, Table S2)
To understand the dehydrogenative coupling steps, treat-
ment of equivalents of 2,5-hexanediol and 1-hexylamine with
complex 2 in toluene under reflux afforded N-hexyl-2,5-
dimethylpyrrole as the major product (90%). Under the same
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Journal of the American Chemical Society
conditions, reaction of an equivalent amount of 2,5-
dimethylpyrrole and 1-hexanol afforded hexyl hexanoate as
the major product and unreacted 2,5-dimethylpyrrole,
indicating that it is not an intermediate in formation of the
N-substituted pyrrole. Thus, the latter is formed by attack of
the primary amine on the formed carbonyl moiety of the diol
followed by water elimination.
In conclusion, two significant reactions based on dehydro-
genative coupling of ammonia and alcohols were developed.
Dehydrogenative coupling of 1,2-diols and ammonia to form
pyrazine derivatives, and the three-component dehydrogen-
ative coupling of 2,5-hexanediol and primary alcohol to form
N-substituted pyrroles, where both reactions were catalyzed by
the acridine-based Ru-pincer complex 1. In both cases,
ammonia was used as the nitrogen source. The acridine-
based PNP-pincer ligand plays a vital role in these trans-
formations, generating the anionic dearomatized PNP-pincer
ligand framework. We believe that these discoveries provide a
new approach toward heteroaromatic synthesis via acceptorless
dehydrogenative coupling by direct use of ammonia.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b08385.
Experimental procedure, GC-MS, NMR spectra of
products (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: david.milstein@weizmann.ac.il.
ORCID
David Milstein: 0000-0002-2320-0262
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This research was supported by the European Research
Council (ERC AdG 692775). D.M. holds the Israel Matz
Professorial Chair. P.D. is thankful to the Planning and
Budgeting Committee (PBC) for a postdoctoral fellowship.
■
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